In the current project, genetic determinants of diabetic nephropathy and related traits are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. Mapping studies, using both genetic linkage and association methods, are being used to identify genomic regions containing variants that confer susceptibility to diabetic kidney disease and related traits. Through collaboration with the multicenter Family Investigation of Nephropathy (FIND) consortium, the genetics of diabetic nephropathy and of diabetic retinopathy are also being studied. FIND was initiated as a genome-wide linkage study and is currently using a genome-wide association strategy to identify regions of interest. Fine-mapping of regions of linkage identified in the Pima study and in FIND is currently underway. In addition, a genome-wide association study for diabetic nephropathy using 1,000,000 single nucleotide polymorphisms has been conducted part of the FIND consortium. Initial analyses showed several regions that potentially harbor nephropathy-susceptibility loci. Replication studies in additional samples identified a variant between CNKSR3 and SCAF8 that was associated with nephropathy at genome-wide statistical significance, and across multiple ethnic groups. Additional follow-up analyses are currently underway. Current efforts are focused on analysis of genome-wide association in the full collection of samples from the FIND consortium; further genome-wide association studies are being conducted in the Pima study. With collaborators, dense linkage disequilibrium maps are being generated in candidate regions for linkage with nephropathy and total cholesterol in Pimas. An genome-wide linkage study using empirical estimates of identity-by-descent (among all individuals), has identified a mis-sense variant in APOC3 that is relatively common in Pimas Indians, and strongly associated with triglycerides. In addition, we found that some DNA methylation profiles from kidney tissue that are predictive of progression of diabetic kidney disease are also observed in peripheral blood; replication studies of this are being pursued. Additional American Indian families informative for association studies of diabetic nephropathy continue to be recruited. In conjunction with collaborators, additional families informative for study of genetics of diabetic nephropathy have been recruited in Micronesia, and genotyping is underway for a genome-wide association study. Genotyping of additional individuals is planned for replication.